Administration of monoclonal antibodies (MoAb) has shown promise as a new treatment modality for human malignancy. However, destruction of malignant cells by MoAb does not always occur, even after successful binding of the antibody to the target cell. A second approach to immunotherapy of malignancy involves the manipulation of the cellular immune system. Lymphokines, such as IL-2, can be used to activate both NK cells and T cells isolated from the blood, spleen, or malignant tumors themselves. The anti-tumor effects of such cells have been well documented both in vitro and in vivo. Toxicity of therapy based on IL-2 alone can be severe and may well limit the clinical utility of this therapy.
Immunotherapy of malignancy that attempts to combine the specificity of antibodies with the power of activated lymphocytes might be more effective and less toxic. One such approach is the use of bispecific antibodies to redirect activated T cell toxicity toward tumor cells expressing the target antigen (Ag.)
Various forms of bispecific antibodies have been produced. These include BSIgG, which are IgG molecules comprising two distinct heavy chains and two distinct light chains that are secreted by so-called "hybrid hybridomas", and heteroantibody conjugates produced by the chemical conjugation of antibodies or antibody fragments of different specificities.
Several investigators have evaluated anti-CD3/anti-tumor bispecific antibody structures as immunotherapeutic agents. Such studies have reported in vitro cytolysis of renal cell carcinoma, melanoma, glioma, lymphoma, leukemia and cells expressing the multidrug-resistance-related glycoprotein. IL-2-activated human peripheral lymphocytes directed by certain anti-CD3/anti-tumor-specific heteroantibody conjugates have also been reported to prevent the growth of human cancer xenografts in nude mice. Studies in vitro, and in vivo in immunodeficient mice bearing human xenografts have reported that certain bispecific antibodies are capable of blocking the growth of both tumor cells bearing certain target antigens and, to some extend, bystander tumor cells that are not recognized by the therapeutic antibody.
The cell membranes of lymphocytes are uniquely constructed and determine such diverse cellular phenotypic characteristics as the suppressor, inducer, or cytolytic function of the cell, the state of activation or stage of differentiation of the cell, and whether the cell belongs to a population that is monoclonal or polyclonal. The vast majority of cellular membrane antigens thus far described on malignant lymphocytes are represented on nonmalignant lymphocytes at some stage of differentiation or activation.
From the foregoing, it is apparent that a need exists for therapeutic agents that are targeted to an antigen found predominantly or exclusively on malignant cells, and which are capable of inducing strong cytolytic activity against such cells. The present invention fulfills this and other needs.